Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 142, Issue 4, Pages 1100-1112Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2017.11.025
Keywords
Neonatal hyperoxia; oxidative stress; asthma; IL-33; ILC2s
Categories
Funding
- Huvis Foundation
- Indiana Pediatric Scientist Award
- [RO1 AI112844]
- [AG047156]
- [HL126647]
- [RO1 AI095282]
- [AI129241]
- [HL62150]
- [RO1 HL62150]
- [RO1 HL117823]
- [RO1 AI128729]
- [R01 CA168814]
- [K12 HD068371]
- [RO1 HL056470]
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Background: Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. Objective: We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. Methods: Mice were exposed to neonatal hyperoxia followed by a period of room air recovery. A group of mice was also intranasally exposed to house dust mite antigen. Assessments were performed at various time points for evaluation of airway hyperresponsiveness, eosinophilia, mucus production, inflammatory gene expression, and T-H and group 2 innate lymphoid cell (ILC2) responses. Sera from term-and preterm-born infants were also collected and levels of IL-33 and type 2 cytokines were measured. Results: Neonatal hyperoxia induced asthma-like features including airway hyperresponsiveness, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic TH responses to house dust mite exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13 but not IL-4 in preterm infants. Conclusions: These data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/ or treat asthma development related to prematurity.
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